P750: CLONAL HEMATOPOIESIS AND EPIGENETIC AGE ACCELERATION IN ELDERLY DANISH TWINS
Authors: M. Tulstrup, M. Soerensen, J. W. Hansen, J. Weischenfeldt, K. Grønbæk, K. Christensen
Journal: HemaSphere (2022)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is commonly ocurring in the elderly and associated with increased morbidity and mortality. CHIP is associated with accelerated epigenetic age (Robertson et al. Curr Biol 29, R786–R787, 2019; Nachun et al., Aging Cell, 20, e13366, 2021) and especially with intrinsic measures of epigenetic age, i.e. measures which reflect cell-type independent effects of aging on DNA methylation, as opposed to extrinsic measures that reflect age-related changes to the immune-cell composition of the peripheral blood. Furthermore, Nachun et al. reported that the combined measure of Hannum and GrimAge acceleration modifies the effect of CHIP mutation status, resulting in strongly increased risk of all-cause mortality in individuals with both CHIP and accelerated Hannum age and GrimAge age. Aims: To replicate and extend these findings in elderly Danish twins, especially investigate gene-specific effects on extrinsic vs. intrinsic estimators and the effect of shared environmental and genetic factors in intra-twin pair analyses. Methods: Blood samples collected from elderly Danish twins (mean age 79 years, range 73–90) in 1997 were analyzed for CHIP mutations using a custom Illumina TruSeq next-generation sequencing panel targeting 21 og the most commonly mutated genes in CHIP. DNA methylation profiling was performed on the Illumina HumanMethylation450K BeadChip. Associations between CHIP and epigenetic age were investigated using linear regression (individual-level analyses) and conditional logistic regression (intra-pair analyses). The interaction between CHIP and epigenetic age acceleration was analysed using Cox proportional hazards regression. Results: Of 308 individuals (154 twin pairs), 116 carried a CHIP mutation. The strongest association with CHIP in individual-level analyses was seen for the Intrinsic Epigenetic Age Acceleration (IEAA) estimator (CHIP carriers 1.40 years older [95% CI: -0.01–2.81]), and in intra-pair analyses Hannum age showed the strongest association (OR 1.1 [1.01–1.19]). In mutation-specific analyses, TET2 mutations were associated with the extrinsic Hannum age estimator in both individual-level (3.12 years [1.07–5.16]) and intra-pair analyses (OR 1.11 [0.99–1.24]). DNMT3A mutations were associated with IEAA in individual-level (1.82 years, [0.07–3.57]) but not intra-pair analysis (OR 1.03, 0.92–1.14). Analyses of logit-transformed VAF were consistent with these results. Individuals with both CHIP and accelerated Hannum and GrimAge estimates did not have an increased mortality risk in our cohort (HR 1.02, [0.70–1.46]). Summary/Conclusion:TET2 mutations were predominantly associated with extrinsic epigenetic age acceleration and the effect remained when controlling for shared factors between co-twins. Conversely, DNMT3A mutations were associated with intrinsic epigenetic age acceleration, and the intra-pair analysis indicated that this association may be due to a shared genetic and/or environmental background. The association between TET2 mutations and extrinsic epigenetic aging indicates that TET2 mutated clones may be drivers of immunosenescence, while the association between DNMT3A mutations and intrinsic epigenetic aging may be due to increased stem cell proliferation rates in individuals with DNMT3A mutations. The CHIP-age acceleration interaction reported by Nachun et al was not replicated, indicating that this mortality model should be used with caution, especially in this age group.